CA1316914C - Process for the preparation of methylene derivatives of androsta-1,4-diene-3,17-dione - Google Patents
Process for the preparation of methylene derivatives of androsta-1,4-diene-3,17-dioneInfo
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- CA1316914C CA1316914C CA000576897A CA576897A CA1316914C CA 1316914 C CA1316914 C CA 1316914C CA 000576897 A CA000576897 A CA 000576897A CA 576897 A CA576897 A CA 576897A CA 1316914 C CA1316914 C CA 1316914C
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- Prior art keywords
- methylenandrosta
- formula
- diene
- dione
- compound
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
- C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J75/00—Processes for the preparation of steroids in general
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- Hydrogenated Pyridines (AREA)
Abstract
A B S T R A C T
The invention relates to a new process for the preparation of known aromatase inhibitors of the following formula wherein each of R1 and R3, independently, is hydrogen or C1-C6 alkyl;
R2 is hydrogen, halogen or C1-C6 alkyl and R4 is hydrogen or fluorine; the process comprising subjecting to Mannich reaction a compound of formula
The invention relates to a new process for the preparation of known aromatase inhibitors of the following formula wherein each of R1 and R3, independently, is hydrogen or C1-C6 alkyl;
R2 is hydrogen, halogen or C1-C6 alkyl and R4 is hydrogen or fluorine; the process comprising subjecting to Mannich reaction a compound of formula
Description
1 3 ~ FC 331 "PROCESS FOR THE PREPARATION OF METHYLENE DERIVATIVES OF
_ ANDROSTA-1,4-DIENE-3,17-DIONE"
The introduction of a methylene, i.e. CH2=, group at the 6-position of 3-oxo- ~ -steroids is a well known process in the art. This type of substitution has been previously achieved by procedures invol~ing a many ste~ synthesis.
The method described by D.Burn et al. in Tetrahedron 20, 597 (1964), for instance, requires the initial conversion of a 3-oxo- ~ -steroid into its 3,~-dienol ether, which is then subjected to Vilsmeier conditions (phosphoryl chlor-ide/dimethylformamide) to yield the iminium salt. After hydrolysis, reduction, and dehydration, the 6-methylene derivative is obtained: Scheme A.
CH-N(CH3)z Cl~3 : ~ : :
,~J~ ~
RO
CH2~H GH2 ~, :
wherein R i 9 lower alkyl.
' - ' '' ' ~L 3 ~ ` 2-~r Published British patent application No. 2177700 and~
European patent application No. 87306125.3 disclose 6-methylene derivatives of androsta-1,4-diene-3,17-dione, which are inhibitors of ~he biotransformation of endogenous androgens to estrogens, i.e. they are aromatase inhibitors.
These compounds are useful, e.g., in the treatment of hormone-dependent tumors, such as breast, endometrial and ovarian cancers.
In the above-mentioned patent applications the methylenation step synthesis is carried out according to the method of K.Annen et al. described in Synthesis 1982,34:Scheme B.
+ H2C~ PCC13lC~C13 R2 OR NaOAs/re~ux~
J~ ;
:
.
;~ wherein ;~, ' . , ' ' . : ' . ~ , '' ' . :. , , ' . ' ' ' :, , . . ' ' ,' , ,' ' ~ : ' `: , ', ' ~ 3 ~ 3.
each of R1 and R3, independently, is hydrogen or C1-C6 alkyl;
R2 is hydrogen, halogen or C1-C6 alkyl;
R4 is hydrogen or fluorine; and R is a lower alkyl group.
The use of formaldehyde acetals with longer or branched alkoxy groups results in a lower yield of product.
Although this method for direct methylenation of 3-oxo-~
steroids provides an economical method for the introduction of a 6-methylene group, it is not possible to obtain yields of products higher than about 40-45%.
Furthermore, if the whole process for the preparation of the corresponding 6-methylenandrosta-1,4-diene-3,17-diones, described in the above-mentioned patent applications is considered, it has to be noticed that:
a. The obtained 3-oxo-6-methylene- ~ -steroids require to be submitted to a long-lasting column chromatography purifi-cation, before being dehydrogenated to the corresponding 6-methylene-a 1~ -derivatives.
b. The best oxidizing agent used in the dehydrogenation step synthesis is dichlorodicyanobenzoquinone ~DDQ), that is very expensive.
~c. The dehydrogenation step synthesis provides yie1dS o~ end-products~not higher than about 40-50%.
d. The obtained end-products require a further long-lasting column chromatography purification.
;:: ~ ~ :
; ' .
. ~ .
~ 4.
Hence the process.described in the above-mentioned patent applications provides yieldsof about 20-25% of end-products.
It requires two long-lasting column chromatography separa-tions; and what is the more the best reducing agent, i.e.
S DDQ, is very expensive. It appears clear that this process cannot be advantageously used for large-scale production.
In investigating both different methods and different inter-mediate products for preparing compounds described in the above-mentioned applications and having the following formula (I) o R ~ ~
(I) : I
_ ANDROSTA-1,4-DIENE-3,17-DIONE"
The introduction of a methylene, i.e. CH2=, group at the 6-position of 3-oxo- ~ -steroids is a well known process in the art. This type of substitution has been previously achieved by procedures invol~ing a many ste~ synthesis.
The method described by D.Burn et al. in Tetrahedron 20, 597 (1964), for instance, requires the initial conversion of a 3-oxo- ~ -steroid into its 3,~-dienol ether, which is then subjected to Vilsmeier conditions (phosphoryl chlor-ide/dimethylformamide) to yield the iminium salt. After hydrolysis, reduction, and dehydration, the 6-methylene derivative is obtained: Scheme A.
CH-N(CH3)z Cl~3 : ~ : :
,~J~ ~
RO
CH2~H GH2 ~, :
wherein R i 9 lower alkyl.
' - ' '' ' ~L 3 ~ ` 2-~r Published British patent application No. 2177700 and~
European patent application No. 87306125.3 disclose 6-methylene derivatives of androsta-1,4-diene-3,17-dione, which are inhibitors of ~he biotransformation of endogenous androgens to estrogens, i.e. they are aromatase inhibitors.
These compounds are useful, e.g., in the treatment of hormone-dependent tumors, such as breast, endometrial and ovarian cancers.
In the above-mentioned patent applications the methylenation step synthesis is carried out according to the method of K.Annen et al. described in Synthesis 1982,34:Scheme B.
+ H2C~ PCC13lC~C13 R2 OR NaOAs/re~ux~
J~ ;
:
.
;~ wherein ;~, ' . , ' ' . : ' . ~ , '' ' . :. , , ' . ' ' ' :, , . . ' ' ,' , ,' ' ~ : ' `: , ', ' ~ 3 ~ 3.
each of R1 and R3, independently, is hydrogen or C1-C6 alkyl;
R2 is hydrogen, halogen or C1-C6 alkyl;
R4 is hydrogen or fluorine; and R is a lower alkyl group.
The use of formaldehyde acetals with longer or branched alkoxy groups results in a lower yield of product.
Although this method for direct methylenation of 3-oxo-~
steroids provides an economical method for the introduction of a 6-methylene group, it is not possible to obtain yields of products higher than about 40-45%.
Furthermore, if the whole process for the preparation of the corresponding 6-methylenandrosta-1,4-diene-3,17-diones, described in the above-mentioned patent applications is considered, it has to be noticed that:
a. The obtained 3-oxo-6-methylene- ~ -steroids require to be submitted to a long-lasting column chromatography purifi-cation, before being dehydrogenated to the corresponding 6-methylene-a 1~ -derivatives.
b. The best oxidizing agent used in the dehydrogenation step synthesis is dichlorodicyanobenzoquinone ~DDQ), that is very expensive.
~c. The dehydrogenation step synthesis provides yie1dS o~ end-products~not higher than about 40-50%.
d. The obtained end-products require a further long-lasting column chromatography purification.
;:: ~ ~ :
; ' .
. ~ .
~ 4.
Hence the process.described in the above-mentioned patent applications provides yieldsof about 20-25% of end-products.
It requires two long-lasting column chromatography separa-tions; and what is the more the best reducing agent, i.e.
S DDQ, is very expensive. It appears clear that this process cannot be advantageously used for large-scale production.
In investigating both different methods and different inter-mediate products for preparing compounds described in the above-mentioned applications and having the following formula (I) o R ~ ~
(I) : I
wherein Rl,R2,R3 and R4 are as defined above, we noticed the method for direct ~ -methylenation of 3-oxo-~ -steroids is applicable to a very wlde variety o~ substrates but not 15~ to androsta-1,4-diene-3,17-dione;derivatlves.
A very interesting observation has been made in the case of a drosta-1,4-dien-17~-ol-3-one derivatives. Indeed surpris-ingly an androsta-1,4-dien-17~-ol-3-one derivative can be , :. , ' . ' .
, , ' . , ~ 3 ~ 5.
subjected to Mannich reaction and the obtained 6-methylene-product can easily be oxidized to an end-product of formula (I), as above defined.
The present invention relates therefore to a new process for the preparation of compounds of formula (I), as herein defined, the process comprising reacting a compound of formula (II) CH
wherein Rl,R2, R3 and R4 are as defined above, with a formal-dehyde source, preferabl~- paraformaldehyde, and an amine : of formula (III~, or a salt thereof, ` ; - NH (III) :~ R
wherein each~R group, which may be the same or different, is lower alkyl, ;90 as:to obtain a compound~of formula (IV~
(IV) 0 ~ R3 .
~ 3 ~
wherein R1, R2~ R3 and R4 are as defined above, and then oxidizing a compound of formula (IV), thus obtained.
In the formulae of the specification the heavy solid lines ( _ ) indicate that a substituent is in the ~ -configuration, i.e. above the plane of the ring; a wavy line ( ~-- ) indicates that a substituent may be either in the ~-configuration, i.e.
below the plane of the ring, or in the ~ -configuration or in both, i.e. a mixture thereof.
In a compound of formula (III) R lower alkyl is e.g. C1-C4 alkyl, preferably it is methyl or ethyl, in particular methyl.
A salt of a compound of a formula (III) is e.g. a salt with an inorganic acid, preferably a hydrohalic acid, in particular the hydrochloric acid.
The reaction of a compound of formula (II) with the formaldehy-de source and a salt of a compound of formula (III) is preferably carried out in a high hoiling alcohol, in particular isopentanol, at temperatures of about 130C or higher than 130C, and for reaction times ranging from about 3 hours to about one day.
In a preferred embodiment of the invention the formaldehyde source is first reacted wlth a salt of a compound of formula (III) and then, to the Mannich salt so obtained, a compound ; of formula (II) is added.
, Oxidation of a compound of formula (IV) can be carried out ~ .
aceording to well known methods, e.g. by Jones or Moffat reagents or by treatment with pyridine dichromate, in polar solvents, such as acetone,~ dimethyl-formamide, dimethyl-sul- ~;
foxide or acetic anhydride. The reaction temperature may ran8e from about -30C to about 50C and the reaction may ~take from about 1 hour to about 1 day. Preferably oxidation .
~ 7.
of a compound of formula (IV) is carried out through Jones reagent, in acetone, at about -10C.
Even if the new process of this invention allows to obtain the desired products of formula (I) in similar, or slightly higher, yields (25-35%), it has the important advantage over the prior art of being both cheap and workable for large scale productionO In fact the intermediate compounds of formula (II) are either commercially available products or can be obtained easily from them. Furthermore the new process does not need any column chromatography separation.
The following Examples illustrate but do not limit the inven-tion.
Example 1 ~; 6-Methylenandrosta-1,4-dien-17B-ol-3-one / compound (IV~): Rl = R2 = R3~=R4 = H7 A stirred mixture of 106.2 g t3.54 mol~ of paraformaldehyde and 346.4 g (4.248 mol) of dimethylamine hydrochloride in 3.6 1 of isopentanol is refluxed (temperature of about 131~C) under nitrogen atmosphere ~in a flask fitted with a Dean-20~ S~tark separator. About 900~ml of a mixture of isopentanoland~separated water are collectéd and discarded. The internal reaction temperature is then lowered~of 10-15C and 90 g (0.314 mol) of boldenone (i.e. androsta-1,4-dien -17~-ol-3-one) are added to the reaction mixture, which is ~gain 2~ heated at reflux ~or 15 hours.
:
~; .
.
~ 3 ~ 8-After cooling, the mixture is treated with 1.2 1 of a 0.1 N
NaOH solution and stirred for 30 min. The organic phase is separated, washed with water and evaporated under vacuum (external temperature of 80C) to yield about 1.6 1 of a suspension.
The supernatant liquor is separated; the resulting precipitate is washed twice with 100 ml portions of hexane and then crystallized from 500 ml of a mixture of ethanol and water t70:30). The filtered white precipitate is dried under 10 vacuum at 40C, thus obtaining 28.7 g (0.963 mol; yield 30.7%) of the title product, m.p. 135-137C.
NMR ( CDC13,~): 0.82 (3H,s), 1.15 (3H,s), 3.67 (lH,m), 4.97 (2H,m), 6.23 (2H,m), 7.08 (lH,d) According to the above described procedure and starting from the appropriate compound of formula (II) one can prepare also the following compounds:
l-methyl-6-methylenandrosta-1;4-dien-17~-ol-3-one;
1-ethyl-6-methylenandrosta-1,4-dien-17~-ol-3-one;
A very interesting observation has been made in the case of a drosta-1,4-dien-17~-ol-3-one derivatives. Indeed surpris-ingly an androsta-1,4-dien-17~-ol-3-one derivative can be , :. , ' . ' .
, , ' . , ~ 3 ~ 5.
subjected to Mannich reaction and the obtained 6-methylene-product can easily be oxidized to an end-product of formula (I), as above defined.
The present invention relates therefore to a new process for the preparation of compounds of formula (I), as herein defined, the process comprising reacting a compound of formula (II) CH
wherein Rl,R2, R3 and R4 are as defined above, with a formal-dehyde source, preferabl~- paraformaldehyde, and an amine : of formula (III~, or a salt thereof, ` ; - NH (III) :~ R
wherein each~R group, which may be the same or different, is lower alkyl, ;90 as:to obtain a compound~of formula (IV~
(IV) 0 ~ R3 .
~ 3 ~
wherein R1, R2~ R3 and R4 are as defined above, and then oxidizing a compound of formula (IV), thus obtained.
In the formulae of the specification the heavy solid lines ( _ ) indicate that a substituent is in the ~ -configuration, i.e. above the plane of the ring; a wavy line ( ~-- ) indicates that a substituent may be either in the ~-configuration, i.e.
below the plane of the ring, or in the ~ -configuration or in both, i.e. a mixture thereof.
In a compound of formula (III) R lower alkyl is e.g. C1-C4 alkyl, preferably it is methyl or ethyl, in particular methyl.
A salt of a compound of a formula (III) is e.g. a salt with an inorganic acid, preferably a hydrohalic acid, in particular the hydrochloric acid.
The reaction of a compound of formula (II) with the formaldehy-de source and a salt of a compound of formula (III) is preferably carried out in a high hoiling alcohol, in particular isopentanol, at temperatures of about 130C or higher than 130C, and for reaction times ranging from about 3 hours to about one day.
In a preferred embodiment of the invention the formaldehyde source is first reacted wlth a salt of a compound of formula (III) and then, to the Mannich salt so obtained, a compound ; of formula (II) is added.
, Oxidation of a compound of formula (IV) can be carried out ~ .
aceording to well known methods, e.g. by Jones or Moffat reagents or by treatment with pyridine dichromate, in polar solvents, such as acetone,~ dimethyl-formamide, dimethyl-sul- ~;
foxide or acetic anhydride. The reaction temperature may ran8e from about -30C to about 50C and the reaction may ~take from about 1 hour to about 1 day. Preferably oxidation .
~ 7.
of a compound of formula (IV) is carried out through Jones reagent, in acetone, at about -10C.
Even if the new process of this invention allows to obtain the desired products of formula (I) in similar, or slightly higher, yields (25-35%), it has the important advantage over the prior art of being both cheap and workable for large scale productionO In fact the intermediate compounds of formula (II) are either commercially available products or can be obtained easily from them. Furthermore the new process does not need any column chromatography separation.
The following Examples illustrate but do not limit the inven-tion.
Example 1 ~; 6-Methylenandrosta-1,4-dien-17B-ol-3-one / compound (IV~): Rl = R2 = R3~=R4 = H7 A stirred mixture of 106.2 g t3.54 mol~ of paraformaldehyde and 346.4 g (4.248 mol) of dimethylamine hydrochloride in 3.6 1 of isopentanol is refluxed (temperature of about 131~C) under nitrogen atmosphere ~in a flask fitted with a Dean-20~ S~tark separator. About 900~ml of a mixture of isopentanoland~separated water are collectéd and discarded. The internal reaction temperature is then lowered~of 10-15C and 90 g (0.314 mol) of boldenone (i.e. androsta-1,4-dien -17~-ol-3-one) are added to the reaction mixture, which is ~gain 2~ heated at reflux ~or 15 hours.
:
~; .
.
~ 3 ~ 8-After cooling, the mixture is treated with 1.2 1 of a 0.1 N
NaOH solution and stirred for 30 min. The organic phase is separated, washed with water and evaporated under vacuum (external temperature of 80C) to yield about 1.6 1 of a suspension.
The supernatant liquor is separated; the resulting precipitate is washed twice with 100 ml portions of hexane and then crystallized from 500 ml of a mixture of ethanol and water t70:30). The filtered white precipitate is dried under 10 vacuum at 40C, thus obtaining 28.7 g (0.963 mol; yield 30.7%) of the title product, m.p. 135-137C.
NMR ( CDC13,~): 0.82 (3H,s), 1.15 (3H,s), 3.67 (lH,m), 4.97 (2H,m), 6.23 (2H,m), 7.08 (lH,d) According to the above described procedure and starting from the appropriate compound of formula (II) one can prepare also the following compounds:
l-methyl-6-methylenandrosta-1;4-dien-17~-ol-3-one;
1-ethyl-6-methylenandrosta-1,4-dien-17~-ol-3-one;
4-methyl-6-methylenandrosta~ 4-dien-17B-ol-3-one;
20 4-chloro-6-methylenandrosta-1,4-dien-17~-ol-3-one;
4-bromo-6-methylenandrosta-1,4-dien-17~-ol-3-one;
4-fluoro-6-methylenandrosta-1,4-dien-17~-ol-3-one;
~4-ohloro~l-methyl-6-methyl~enandrosta-1,4-dien-17B-ol-3-one;
4-bromo-1-methyl-6-methylenandrosta-1,4-dien-17~-ol-3-one;
~4-fluoro-1-methyl-6~methylenandrosta-l,4-dien-17~-ol-3-one;
, 9.
Analogously one can obtain the following 7-and/or I6-sub-stituted derivatives as single epimers or as a mixture thereof 1,7-dimethyl-16-fluoro-6-methylenandrosta-1,4-dien-17B-ol-3-one;
16-fluoro-6-methylenandrosta-1,4-dien-17B-ol-3-one;
16-fluoro-1-methyl-6 methylenandrosta-1,4-dien-17B-ol-3-one;
1,7-dimethyl-6-methylenandrosta-1,4-dien-17B-ol-3-one 16-fluoro-7-methyl-6-methylenandrosta-1,4-dien-17B-ol-3-one;
10 4,16-difluoro-1,7-dimethyl-6-methylenandrosta-1,4-dien-17B-ol-3-one 9 and 7-methyl-6-methylen~ost-1,4~en-17B-ol-3-one.
:
Example 2 6-methylenandrosta-1,4-diene-3,17-dione 15 [ Compound (I): Rl = R2 = R3 = R4 = H 7 ~ ~
To a stirred solution of~28.7 g (0.963 mol~ of 6-methylen-androsta-1,4-dien-17B-ol-3-one in 700 ml of acetone, at -lO~C, are added~35 ml~of Jones reagent dropwise.
When~the~add~tlon is over,~the~rèac~tion;mlxture is stirred for further~10 min and then careiully ~treated with 50 ml of isopropanol.~After one hour oi addit~ional stirring, the resultlng inorganic preclpltate~ls flltered off and thoroughly : : :
3 3~ s ~7~ lo.
washed with acetone. The combined filtrate and washings are stirred with 100 8 Of sodium bicarbonate for 1 hour, filtered and evaporated under vacuum. The resulting solid is taken up with 500 ml of water, filtered off, washed with water and then dried under vacuum at about 40C, thus obtaining 25 g o~ a solid. Further purification by crystallization from 300 ml of a 65 35 mixture of ethanol and water gives 22.4 g (0.76 mol; yield 79%) of the title compound, m.p. 192-195C.
Found C 81.01; H 8.16. C20H2402 requires: C 81.04; H 8.05;
U.V. (EtOH, ~ 247 ~ = 13750).
NMR (CDCl3,~): 0.94 (3H,s), 1.17 (3H,s), 5.04 (2H,m), 6.18 (lH, br s), 6.25 (lH,dd), 7.09 (lH,d).
Using the same procedure and starting from the appropriate compound of formula (IV) one can prepare the following end--products:
1-methyl-6-~ethylenandrosta-1~4-diene-3,17-dione, m.p.:178-180C;
Found: C 81.1~; H 8.37. C21H2602 requires: C 81.25; H 8.44;
1-ethyl-6-methylenandrosta-1,4-diene-3,17-dione, Found: C 81.32; H 8.62. C22H2802 requires: C 81.44; H 8.70;
20 4-methyl-6-methylenandrosta-1,4-diene-~3,17-dione;
Found: C 81.15; H 8.32. C21H2602 requires: C 81.25; H 8.44;
4-chloro-6-methylenandrosta-1,4-diene-3,17-dione, m.p.:148-150C;
Found: C 72.40,~H 6.91, Cl 10.53; C20H23Cl02 requires:
C 72.61, H 7.01, C1 10.72.
25 N.M.R.(CDC13,~ 0.84 (3Hjs);~1,24~(3H,s); 5.13 (lH,s); 6.37 (lH,d);
7.08 (lH,d) : ~ :
.
~ , ~ 3 ~ 3~
MS (m/z): 330.
4-bromo-6-methylenandrosta-1,4-diene-3,17-dione, Found: C 63.90; H 6.03; Br 21.15. C20H23BrO2 requires: C 54-00;
H 6.18; Br 21.29;
4-fluoro-6-methylenandrosta-1,4-diene-3,17-dione, Found: C 76.35; H 7.34; F 6.01. C20H23F02 requires: C 76.41;
H 7.37; F 6~04.
4-chloro-1-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
4-bromo-1-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
4-fluoro-1-methyl-6-methylenandrosta-1,4-diene-3,17-dione, Found: C 76.75; H 7.62; F 5.71. C2iH25F02 requires: C 76.80;
H 7.67; F 5.79;
Analogously one can obtain the following 7- and/or 16-sub-stituted derivatives as single epimers or as a mixture thereof 1,7-dimethyl-16 -fluoro-6-methylenandrosta-1,4-diene-3,17-dione;
~Found C 77.05, ~ 7-80j F 5.45. C22H27F02 requires C 77.16, H 7~95, F 5.55.
~ ~16-f}uoro-6-methylenandrosta-1,4-diene-3,17-dione;
:
16-fluoro-1-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
1,7 dimethyl-6-methylenandrosta-1,4-diene-3,17-dione;
~7 methyl-6-methylenandrosta-1,4-diene-3,17-dione;
16-fluoro-7-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
25 ~ 16 fluoro-4-chloro-1,7 - dimethyl-6-methylenandrosta-1,4-diene-3,17-dione~
.
', : .
:. ' , ' ' ~ ~ .
~ ~ ',.. ..
3 ~ ~ !r~ 12.
Found: C 70.05, H 6.89, Cl 9.32, F 4.99. C22H26CIF02 requires:
C 70.11, H 6.95, Cl 9.41, F 5.04.
16-fluoro-4-chloro-6-methylenandrosta-1,4-diene-3,17-dione;
4,16-difluoro-6-methylenandrosta-1,4-diene-3,17-dione;
4-chloro-7-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
4-fluoro-7-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
16-fluoro-4-chloro-1-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
4,16-difluoro-1-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
4-chloro-1,7-dimethyl-6-methylenandrosta-1,4-diene-3,17-dione;
4-~luoro-1,7-dimethyl-6-methylenandrosta-1,4-diene-3,17-dione;
16-fluoro-4-chloro-7-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
4,16-difluoro-7-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
and 4,16-difluoro-1,7-dimethyl-6-methylenandrosta-1,4-diene-3,17-dione.
, . ~ :
j ~ .
, ~; :
i~:
j , : :
:
' , :
, '
20 4-chloro-6-methylenandrosta-1,4-dien-17~-ol-3-one;
4-bromo-6-methylenandrosta-1,4-dien-17~-ol-3-one;
4-fluoro-6-methylenandrosta-1,4-dien-17~-ol-3-one;
~4-ohloro~l-methyl-6-methyl~enandrosta-1,4-dien-17B-ol-3-one;
4-bromo-1-methyl-6-methylenandrosta-1,4-dien-17~-ol-3-one;
~4-fluoro-1-methyl-6~methylenandrosta-l,4-dien-17~-ol-3-one;
, 9.
Analogously one can obtain the following 7-and/or I6-sub-stituted derivatives as single epimers or as a mixture thereof 1,7-dimethyl-16-fluoro-6-methylenandrosta-1,4-dien-17B-ol-3-one;
16-fluoro-6-methylenandrosta-1,4-dien-17B-ol-3-one;
16-fluoro-1-methyl-6 methylenandrosta-1,4-dien-17B-ol-3-one;
1,7-dimethyl-6-methylenandrosta-1,4-dien-17B-ol-3-one 16-fluoro-7-methyl-6-methylenandrosta-1,4-dien-17B-ol-3-one;
10 4,16-difluoro-1,7-dimethyl-6-methylenandrosta-1,4-dien-17B-ol-3-one 9 and 7-methyl-6-methylen~ost-1,4~en-17B-ol-3-one.
:
Example 2 6-methylenandrosta-1,4-diene-3,17-dione 15 [ Compound (I): Rl = R2 = R3 = R4 = H 7 ~ ~
To a stirred solution of~28.7 g (0.963 mol~ of 6-methylen-androsta-1,4-dien-17B-ol-3-one in 700 ml of acetone, at -lO~C, are added~35 ml~of Jones reagent dropwise.
When~the~add~tlon is over,~the~rèac~tion;mlxture is stirred for further~10 min and then careiully ~treated with 50 ml of isopropanol.~After one hour oi addit~ional stirring, the resultlng inorganic preclpltate~ls flltered off and thoroughly : : :
3 3~ s ~7~ lo.
washed with acetone. The combined filtrate and washings are stirred with 100 8 Of sodium bicarbonate for 1 hour, filtered and evaporated under vacuum. The resulting solid is taken up with 500 ml of water, filtered off, washed with water and then dried under vacuum at about 40C, thus obtaining 25 g o~ a solid. Further purification by crystallization from 300 ml of a 65 35 mixture of ethanol and water gives 22.4 g (0.76 mol; yield 79%) of the title compound, m.p. 192-195C.
Found C 81.01; H 8.16. C20H2402 requires: C 81.04; H 8.05;
U.V. (EtOH, ~ 247 ~ = 13750).
NMR (CDCl3,~): 0.94 (3H,s), 1.17 (3H,s), 5.04 (2H,m), 6.18 (lH, br s), 6.25 (lH,dd), 7.09 (lH,d).
Using the same procedure and starting from the appropriate compound of formula (IV) one can prepare the following end--products:
1-methyl-6-~ethylenandrosta-1~4-diene-3,17-dione, m.p.:178-180C;
Found: C 81.1~; H 8.37. C21H2602 requires: C 81.25; H 8.44;
1-ethyl-6-methylenandrosta-1,4-diene-3,17-dione, Found: C 81.32; H 8.62. C22H2802 requires: C 81.44; H 8.70;
20 4-methyl-6-methylenandrosta-1,4-diene-~3,17-dione;
Found: C 81.15; H 8.32. C21H2602 requires: C 81.25; H 8.44;
4-chloro-6-methylenandrosta-1,4-diene-3,17-dione, m.p.:148-150C;
Found: C 72.40,~H 6.91, Cl 10.53; C20H23Cl02 requires:
C 72.61, H 7.01, C1 10.72.
25 N.M.R.(CDC13,~ 0.84 (3Hjs);~1,24~(3H,s); 5.13 (lH,s); 6.37 (lH,d);
7.08 (lH,d) : ~ :
.
~ , ~ 3 ~ 3~
MS (m/z): 330.
4-bromo-6-methylenandrosta-1,4-diene-3,17-dione, Found: C 63.90; H 6.03; Br 21.15. C20H23BrO2 requires: C 54-00;
H 6.18; Br 21.29;
4-fluoro-6-methylenandrosta-1,4-diene-3,17-dione, Found: C 76.35; H 7.34; F 6.01. C20H23F02 requires: C 76.41;
H 7.37; F 6~04.
4-chloro-1-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
4-bromo-1-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
4-fluoro-1-methyl-6-methylenandrosta-1,4-diene-3,17-dione, Found: C 76.75; H 7.62; F 5.71. C2iH25F02 requires: C 76.80;
H 7.67; F 5.79;
Analogously one can obtain the following 7- and/or 16-sub-stituted derivatives as single epimers or as a mixture thereof 1,7-dimethyl-16 -fluoro-6-methylenandrosta-1,4-diene-3,17-dione;
~Found C 77.05, ~ 7-80j F 5.45. C22H27F02 requires C 77.16, H 7~95, F 5.55.
~ ~16-f}uoro-6-methylenandrosta-1,4-diene-3,17-dione;
:
16-fluoro-1-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
1,7 dimethyl-6-methylenandrosta-1,4-diene-3,17-dione;
~7 methyl-6-methylenandrosta-1,4-diene-3,17-dione;
16-fluoro-7-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
25 ~ 16 fluoro-4-chloro-1,7 - dimethyl-6-methylenandrosta-1,4-diene-3,17-dione~
.
', : .
:. ' , ' ' ~ ~ .
~ ~ ',.. ..
3 ~ ~ !r~ 12.
Found: C 70.05, H 6.89, Cl 9.32, F 4.99. C22H26CIF02 requires:
C 70.11, H 6.95, Cl 9.41, F 5.04.
16-fluoro-4-chloro-6-methylenandrosta-1,4-diene-3,17-dione;
4,16-difluoro-6-methylenandrosta-1,4-diene-3,17-dione;
4-chloro-7-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
4-fluoro-7-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
16-fluoro-4-chloro-1-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
4,16-difluoro-1-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
4-chloro-1,7-dimethyl-6-methylenandrosta-1,4-diene-3,17-dione;
4-~luoro-1,7-dimethyl-6-methylenandrosta-1,4-diene-3,17-dione;
16-fluoro-4-chloro-7-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
4,16-difluoro-7-methyl-6-methylenandrosta-1,4-diene-3,17-dione;
and 4,16-difluoro-1,7-dimethyl-6-methylenandrosta-1,4-diene-3,17-dione.
, . ~ :
j ~ .
, ~; :
i~:
j , : :
:
' , :
, '
Claims (4)
1. A process for the preparation of a compound of formula (I) (I) wherein each of R1 and R3, independently, is hydrogen or C1-C6 alkyl;
R2 is hydrogen, halogen or C1-C6 alkyl; and R4 is hydrogen or fluorine;
the process comprising reacting a compound of formula (II) (II) wherein R1, R2, R3 and R4 are as defined above, with a formaldehyde source and an amine of formula (III), or a salt thereof, (III) wherein each R group, which May be the same or different, is lower alkyl, so as to obtain a compound of formula (IV) (IV) wherein R1, R2, R3 and R4 are as defined above, and oxidizing a compound of formula (IV) thus obtained.
R2 is hydrogen, halogen or C1-C6 alkyl; and R4 is hydrogen or fluorine;
the process comprising reacting a compound of formula (II) (II) wherein R1, R2, R3 and R4 are as defined above, with a formaldehyde source and an amine of formula (III), or a salt thereof, (III) wherein each R group, which May be the same or different, is lower alkyl, so as to obtain a compound of formula (IV) (IV) wherein R1, R2, R3 and R4 are as defined above, and oxidizing a compound of formula (IV) thus obtained.
2. A process according to claim 1, wherein the compound of formula (II) is reacted in isopentanol at a temperature of at least 130°C with the formaldehyde source and a salt formed between a hydrohalic acid and the amine of formula (III).
3. A process according to claim 1, wherein the compound of formula (II) is reacted with a Mannich salt obtained by reacting the formaldehyde source with a salt formed between a hydrohalic acid and the amine of formula (III).
4. A process according to any one of claims 1 to 3, wherein the formaldehyde source is paraformaldehyde.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB878721383A GB8721383D0 (en) | 1987-09-11 | 1987-09-11 | Preparation of methylene derivatives |
| GB8721383 | 1987-09-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1316914C true CA1316914C (en) | 1993-04-27 |
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ID=10623618
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000576897A Expired - Lifetime CA1316914C (en) | 1987-09-11 | 1988-09-09 | Process for the preparation of methylene derivatives of androsta-1,4-diene-3,17-dione |
Country Status (16)
| Country | Link |
|---|---|
| US (1) | US4876045A (en) |
| EP (1) | EP0307134B1 (en) |
| JP (1) | JP2791046B2 (en) |
| KR (1) | KR970005315B1 (en) |
| AT (1) | ATE78488T1 (en) |
| AU (1) | AU602608B2 (en) |
| CA (1) | CA1316914C (en) |
| DE (1) | DE3872995T2 (en) |
| ES (1) | ES2051858T3 (en) |
| FI (1) | FI884087A (en) |
| GB (1) | GB8721383D0 (en) |
| GR (1) | GR3005296T3 (en) |
| HU (1) | HU199156B (en) |
| IL (1) | IL87657A (en) |
| SU (1) | SU1681731A3 (en) |
| UA (1) | UA6044A1 (en) |
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| GB9201224D0 (en) * | 1992-01-21 | 1992-03-11 | Erba Carlo Spa | Difluoromethylenandrostenone derivatives and process for their preparation |
| WO2001004342A1 (en) * | 1999-07-07 | 2001-01-18 | Pharmacia & Upjohn Company | Process to prepare exemestane |
| CN1304413C (en) * | 2002-10-24 | 2007-03-14 | 上海华拓医药科技发展有限公司 | Process for preparing anti-cancer medicine Exemestane |
| US8183401B2 (en) * | 2004-01-16 | 2012-05-22 | Cedarburg Pharmaceuticals, Inc. | Exemestane and its intermediates and methods of making the same |
| US10174070B2 (en) | 2005-09-30 | 2019-01-08 | Endece Llc | 6-substituted estradiol derivatives and methods of use |
| US20070225354A1 (en) * | 2006-03-21 | 2007-09-27 | Eric Marchewitz | Use of dihydrolipoamide for enhancing physical performance |
| US7569719B1 (en) * | 2006-10-25 | 2009-08-04 | Loctite (R&D) Limited | Method of preparing electron deficient olefins |
| US20080275259A1 (en) * | 2007-05-04 | 2008-11-06 | Scinopharm Taiwan, Ltd | Process for preparing aromatase inhibitors |
| SI2170329T1 (en) * | 2007-06-25 | 2015-03-31 | Scinopharm Taiwan Ltd. | Process for preparing a crystalline polymorph of 7-ethyl-10-hydroxycamptothecin |
| CN101686969A (en) * | 2007-06-25 | 2010-03-31 | 台湾神隆股份有限公司 | crystalline polymorph of exemestane |
| CA2703596A1 (en) * | 2007-10-24 | 2009-04-30 | Loctite (R&D) Limited | Activated methylene reagents and curable compositions prepared therefrom |
| US8686105B2 (en) | 2007-10-24 | 2014-04-01 | Henkel IP & Holding GmbH | Adhesive systems using imines and salts thereof, precursors to electron deficient olefins and coreactants therefor |
| US7973119B1 (en) | 2007-10-24 | 2011-07-05 | Loctite (R&D) Limited | Adhesive systems using imines and salts thereof and precursurs to electron deficient olefins |
| US8053589B1 (en) * | 2007-10-24 | 2011-11-08 | Henkel Ireland Limited | Imines and methods of preparing electron deficient olefins using such novel imines |
| JP5639892B2 (en) | 2007-10-24 | 2014-12-10 | ヘンケル アイルランド リミテッド | Electron deficient olefin |
| US10196471B1 (en) | 2008-10-24 | 2019-02-05 | Henkel IP & Holding GmbH | Curable composition having an electron deficient olefin |
| US8399698B1 (en) | 2008-10-24 | 2013-03-19 | Henkel Ireland Limited | Substituted activated methylene reagents and methods of using such reagents to form electron deficient olefins |
| EP2429299B1 (en) | 2009-05-01 | 2016-06-01 | Celloxess Llc | Treating male infertility secondary to sperm oxidative stress |
| ES2605960T3 (en) | 2010-09-14 | 2017-03-17 | Endece, Llc | 6-substituted desmethyl estradiol derivatives as RE-beta agonists |
| CN105085599A (en) * | 2014-05-16 | 2015-11-25 | 绍兴文理学院 | Exemestane intermediate 17,17-ethyldioxy-6-methyleneandrost-1,4-diene-3-ketone and preparation method and application thereof |
| CN105294807A (en) * | 2014-06-26 | 2016-02-03 | 浙江医药股份有限公司新昌制药厂 | Exemestane intermediate oxime compound, and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE3004508C2 (en) * | 1980-02-05 | 1981-12-10 | Schering Ag Berlin Und Bergkamen, 1000 Berlin | Process for the preparation of 6-methylene steroids |
| GB8517360D0 (en) * | 1985-07-09 | 1985-08-14 | Erba Farmitalia | Substituted androsta-1,4-diene-3,17-diones |
-
1987
- 1987-09-11 GB GB878721383A patent/GB8721383D0/en active Pending
-
1988
- 1988-09-01 EP EP88308103A patent/EP0307134B1/en not_active Expired - Lifetime
- 1988-09-01 DE DE8888308103T patent/DE3872995T2/en not_active Expired - Lifetime
- 1988-09-01 ES ES88308103T patent/ES2051858T3/en not_active Expired - Lifetime
- 1988-09-01 AT AT88308103T patent/ATE78488T1/en active
- 1988-09-02 IL IL87657A patent/IL87657A/en not_active IP Right Cessation
- 1988-09-06 FI FI884087A patent/FI884087A/en not_active Application Discontinuation
- 1988-09-07 AU AU21980/88A patent/AU602608B2/en not_active Expired
- 1988-09-08 JP JP63225508A patent/JP2791046B2/en not_active Expired - Lifetime
- 1988-09-09 HU HU884665A patent/HU199156B/en unknown
- 1988-09-09 SU SU884356486A patent/SU1681731A3/en active
- 1988-09-09 UA UA4356486A patent/UA6044A1/en unknown
- 1988-09-09 CA CA000576897A patent/CA1316914C/en not_active Expired - Lifetime
- 1988-09-09 KR KR1019880011641A patent/KR970005315B1/en not_active IP Right Cessation
- 1988-09-12 US US07/242,854 patent/US4876045A/en not_active Expired - Lifetime
-
1992
- 1992-07-29 GR GR920401628T patent/GR3005296T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP0307134B1 (en) | 1992-07-22 |
| GB8721383D0 (en) | 1987-10-21 |
| DE3872995D1 (en) | 1992-08-27 |
| ATE78488T1 (en) | 1992-08-15 |
| FI884087A (en) | 1989-03-12 |
| SU1681731A3 (en) | 1991-09-30 |
| AU2198088A (en) | 1989-03-16 |
| KR890005141A (en) | 1989-05-13 |
| JPH01104095A (en) | 1989-04-21 |
| UA6044A1 (en) | 1994-12-29 |
| GR3005296T3 (en) | 1993-05-24 |
| JP2791046B2 (en) | 1998-08-27 |
| IL87657A0 (en) | 1989-02-28 |
| IL87657A (en) | 1993-02-21 |
| DE3872995T2 (en) | 1992-12-10 |
| AU602608B2 (en) | 1990-10-18 |
| ES2051858T3 (en) | 1994-07-01 |
| HUT48273A (en) | 1989-05-29 |
| KR970005315B1 (en) | 1997-04-15 |
| EP0307134A1 (en) | 1989-03-15 |
| HU199156B (en) | 1990-01-29 |
| US4876045A (en) | 1989-10-24 |
| FI884087A0 (en) | 1988-09-06 |
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